Gastroesophageal reflux disease (GERD) and its troublesome complications constitute serious diagnostic and management challenges to the development of safe feeding and airway protection strategies among infants convalescing in the neonatal intensive care units; thus contributing to prolonged lengths of stay, recurrent hospitalizations, and death. GERD is frequently diagnosed by inadequate criteria, and the relative risks, benefits and indications of GERD therapies are unclear. Significant gaps in knowledge exist in understanding the complex causal or adaptive aerodigestive protective reflex mechanisms implicated in GERD in infants. The long-term goal is to improve digestive health, nutrition, and infant development through the design of simplified personalized treatment paradigms by better understanding the pathophysiology of aerodigestive reflexes. The current objective is to conduct a prospective single center randomized blinded controlled trial comparing the short term effects of our innovative feeding strategy bundle versus standard feeding approach. The central unifying hypothesis is that our innovative feeding strategy bundle will modify the overlapping functions of several aerodigestive reflexes responsible for esophageal clearance and airway protection to improve clinical outcomes in these patients. This hypothesis is formulated based on our prior work during the R01 funding period. The rationale for this proposal is to minimize morbidities from GERD by understanding the integration of afferent-efferent relationships of aerodigestive reflexes in relation to infant feeding approaches. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Comparison of the clinical outcomes of standard feeding approach with the innovative feeding strategy bundle, and 2) Determination of the pathophysiological mechanism of success or failure to either therapy. Under aim-1, we will test the hypothesis that the innovative feeding strategy bundle is more effective in achieving the oral feeding success and decrease in infant-GER-questionnaire-revised symptom scores. Under aim-2, we will test the hypothesis and validate results from the preliminary data by utilizing our diagnostic tools to identify difference between the two study arms in regards to aero-digestive reflexes, esophageal clearance mechanisms, enteric neuromotor markers of swallowing, and pH-impedance-symptom indices. The approach is innovative, in that we use state-of-the-art methods including multimodal esophageal sensory provocation methods, videomanometry, pH-Impedance methods, symptom indices, glottal ultrasonography, and innovative feeding strategy. The proposed research is significant, because knowledge gained will provide the scientific and economic rationale for future multicenter effectiveness trials to refine therapies for GERD. New benchmarks to develop preventative and therapeutic strategies for GERD in infants are anticipated, which will positively impact the quality of life for infants and parents. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the pathophysiology based infant feeding practices will overcome the burden of aerodigestive suffering in infants with gastroesophageal reflux disease. The proposed studies will overcome the critical barrier to progress by providing the scientific and economic rationale for the development of safe feeding paradigms in vulnerable infants, and enhances digestive health in infants, all relevant to the mission of NIH (NIDDK).